One of the earliest and most profound deficits that results from traumatic brain injury (TBI) comes from damage to the vascular networks that ultimately underlies much of the progressive pathophysiology associated with TBI. Unfortunately, little is known of the cellular signs and responses that regulate vessel integrity and/or remodeling in the injured brain. The objective of this study is to examine the role of ephrinB3 and EphB3 in vascular injury and regrowth following TBI. B-class ephrin and Eph receptors are both membrane bound proteins that initiate bidirectional signals during cell-cell interactions. In the developing nervous system, ephrinB2-EphB4 interactions have been shown to play essential roles in forming arterial-venous specifications to determine vessel identity; however, the role of other ephrins/Ephs is less clear. Our preliminary findings suggest that ephrinB3 and EphB3 may also play critical roles in angiogenesis in the cerebral cortex. We hypothesize that a subpopulation of endothelial cells (ECs) and pericytes express EphB3 and ephrinB3, respectively, and signal to restrict EC proliferation and vascular regrowth in the injured cortex. To test this hypothesis we will examine the spatiotemporal changes in ephrinB3/EphB3, effects of ephrinB3/EphB3 on vascular stability and regrowth using loss- and gain-of-function approaches, and influences of vascular growth on the survival of other residential cells in the TBI penumbra. We will also take advantage of flow cytometry, EC-specific inducible mice, light-sheet microscopy, newly developed 3-D quantification, as well as behavior analysis. These studies will provide a novel approach to examine the influence of vascular growth on injury progression in the brain.